Biological and pathological mechanisms leading to the birth of a small vulnerable newborn.

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments.

Pregnancy outcomes and vaccine effectiveness during the period of omicron as the variant of concern, INTERCOVID-2022: a multinational, observational study.

BACKGROUND: In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern. METHODS: INTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile. FINDINGS: We enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose. INTERPRETATION: COVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority. FUNDING: None.

Maternal vaccination against COVID-19 and neonatal outcomes during Omicron: INTERCOVID-2022 study.

BACKGROUND: In early 2023, when Omicron was the variant of concern, we showed that vaccinating pregnant women decreased the risk for severe COVID-19-related complications and maternal morbidity and mortality. OBJECTIVE: This study aimed to analyze the impact of COVID-19 during pregnancy on newborns and the effects of maternal COVID-19 vaccination on neonatal outcomes when Omicron was the variant of concern. STUDY DESIGN: INTERCOVID-2022 was a large, prospective, observational study, conducted in 40 hospitals across 18 countries, from November 27, 2021 (the day after the World Health Organization declared Omicron the variant of concern) to June 30, 2022, to assess the effect of COVID-19 in pregnancy on maternal and neonatal outcomes and to assess vaccine effectiveness. Women diagnosed with laboratory-confirmed COVID-19 during pregnancy were compared with 2 nondiagnosed, unmatched women recruited concomitantly and consecutively during pregnancy or at delivery. Mother-newborn dyads were followed until hospital discharge. The primary outcomes were a neonatal positive test for COVID-19, severe neonatal morbidity index, severe perinatal morbidity and mortality index, preterm birth, neonatal death, referral to neonatal intensive care unit, and diseases during the neonatal period. Vaccine effectiveness was estimated with adjustment for maternal risk profile. RESULTS: We enrolled 4707 neonates born to 1577 (33.5%) mothers diagnosed with COVID-19 and 3130 (66.5%) nondiagnosed mothers. Among the diagnosed mothers, 642 (40.7%) were not vaccinated, 147 (9.3%) were partially vaccinated, 551 (34.9%) were completely vaccinated, and 237 (15.0%) also had a booster vaccine. Neonates of booster-vaccinated mothers had less than half (relative risk, 0.46; 95% confidence interval, 0.23-0.91) the risk of being diagnosed with COVID-19 when compared with those of unvaccinated mothers; they also had the lowest rates of preterm birth, medically indicated preterm birth, respiratory distress syndrome, and number of days in the neonatal intensive care unit. Newborns of unvaccinated mothers had double the risk for neonatal death (relative risk, 2.06; 95% confidence interval, 1.06-4.00) when compared with those of nondiagnosed mothers. Vaccination was not associated with any congenital malformations. Although all vaccines provided protection against neonatal test positivity, newborns of booster-vaccinated mothers had the highest vaccine effectiveness (64%; 95% confidence interval, 10%-86%). Vaccine effectiveness was not as high for messenger RNA vaccines only. Vaccine effectiveness against moderate or severe neonatal outcomes was much lower, namely 13% in the booster-vaccinated group (all vaccines) and 25% and 28% in the completely and booster-vaccinated groups, respectively (messenger RNA vaccines only). Vaccines were fairly effective in protecting neonates when given to pregnant women ≤100 days (14 weeks) before birth; thereafter, the risk increased and was much higher after 200 days (29 weeks). Finally, none of the neonatal practices studied, including skin-to-skin contact and direct breastfeeding, increased the risk for infecting newborns. CONCLUSION: When Omicron was the variant of concern, newborns of unvaccinated mothers had an increased risk for neonatal death. Neonates of vaccinated mothers had a decreased risk for preterm birth and adverse neonatal outcomes. Because the protective effect of COVID-19 vaccination decreases with time, to ensure that newborns are maximally protected against COVID-19, mothers should receive a vaccine or booster dose no more than 14 weeks before the expected date of delivery.

Effect of a Brief Supportive and Educational Intervention on the Psychological Well-Being of Mothers with Babies in Neonatal Wards of a Tertiary Hospital in Ibadan, Nigeria.

OBJECTIVE: To assess the effect of a supportive educational intervention on the psychological wellbeing of mothers whose babies were admitted to Neonatal Care Unit (NCU) in Nigeria. METHODS: Controlled trial involving 41 mothers whose babies were consecutively admitted into two NCUs (21 in the intervention group and 19 controls). The intervention group received two group-based sessions which included psychological coping strategies, and familiarity with NCU environment, equipment, personnel and procedures. The control group received usual care. Outcome measures were depressive symptoms (Edinburg Postnatal Depression Scale-EPDS), stress-related to NCU (Parental Stressor Scale: Neonatal Intensive Care Unit-PSS: NICU) and post-traumatic symptoms (Impact Event Scale-Revised-IES-R). RESULTS: Difference-in-Differences (DiD) analysis showed a difference of -4.70 in PSS: NICU score in favour of the intervention group which was statistically significant [F(3, 75) = 9.47, p < 0.0001, R2 = 0.28]. The differences in EPDS (0.91) and IES-R (2.55) were not statistically significant [F(3, 75) = 10.10, p = 0.74] and [F(3, 75) = 10.13, p = 0.73], respectively. All the mothers in the treatment group expressed satisfaction with the intervention. CONCLUSION: This brief group-based supportive educational intervention for mothers with babies in NCU was feasible, acceptable and helpful in reducing stress related to NCU. Larger controlled trials are recommended to establish the generalizability of these findings in this region. LAY SUMMARY: Babies born too early and or with complications require admission to special hospital called Neonatal Care Unit (NCU) to help them to survive. However, parents whose babies are admitted to NCU can find the experience frightening. We examined how to reduce the fear and stress mothers in Nigeria experience when their babies are admitted to NCU.We had two groups of mothers. The first group made up of 21 mothers was taught how to cope with the stress of having a baby in NCU. They were also shown how the various equipment in the NCU work, what the staff in NCU do and what types of things need to be done to help their babies. The second group of 19 mothers received usual care but did not have the extra teaching the first group received. After 2 weeks, we checked the level of depression and stress the mothers in both groups had compared with the level before the first group received the extra teaching.We found that mothers in the first group who received the extra teaching were less stressed about having their babies in the NCU compared with the mothers that did not receive the teaching.

Early Use of Antibiotics Is Associated with a Lower Incidence of Necrotizing Enterocolitis in Preterm, Very Low Birth Weight Infants: The NEOMUNE-NeoNutriNet Cohort Study.

OBJECTIVE: To determine whether commencement of antibiotics within 3 postnatal days in preterm, very low birth weight (VLBW; ≤1500 g) infants is associated with the development of necrotizing enterocolitis (NEC). STUDY DESIGN: Preplanned statistical analyses were done to study the association between early antibiotic treatment and later NEC development, using the NEOMUNE-NeoNutriNet cohort of VLBW infants from 13 neonatal intensive care units (NICUs) in 5 continents (n = 2831). NEC incidence was compared between infants who received early antibiotics and those who did not, with statistical adjustments for NICU, gestational age, birth weight, sex, delivery mode, antenatal steroid use, Apgar score, and type and initiation of enteral nutrition. RESULTS: The incidence of NEC was 9.0% in the group of infants who did not receive early antibiotics (n = 269), compared with 3.9% in those who did receive early antibiotics (n = 2562). The incidence remained lower in the early antibiotic group after stepwise statistical adjustments for NICU (OR, 0.57; 95% CI, 0.35-0.94, P < .05) and other potential confounders (OR, 0.25; 95% CI, 0.12-0.47; P < .0001). CONCLUSIONS: In this large international cohort of preterm VLBW infants, a small proportion of infants did not receive antibiotics just after birth, and these infants had a higher incidence of NEC. It is important to better understand the role of such variables as time, type, and duration of antibiotic treatment on NEC incidence, immune development, gut colonization, and antibiotic resistance in the NICU.

Oxygen systems to improve clinical care and outcomes for children and neonates: A stepped-wedge cluster-randomised trial in Nigeria.

BACKGROUND: Improving oxygen systems may improve clinical outcomes for hospitalised children with acute lower respiratory infection (ALRI). This paper reports the effects of an improved oxygen system on mortality and clinical practices in 12 general, paediatric, and maternity hospitals in southwest Nigeria. METHODS AND FINDINGS: We conducted an unblinded stepped-wedge cluster-randomised trial comparing three study periods: baseline (usual care), pulse oximetry introduction, and stepped introduction of a multifaceted oxygen system. We collected data from clinical records of all admitted neonates (<28 days old) and children (28 days to 14 years old). Primary analysis compared the full oxygen system period to the pulse oximetry period and evaluated odds of death for children, children with ALRI, neonates, and preterm neonates using mixed-effects logistic regression. Secondary analyses included the baseline period (enabling evaluation of pulse oximetry introduction) and evaluated mortality and practice outcomes on additional subgroups. Three hospitals received the oxygen system intervention at 4-month intervals. Primary analysis included 7,716 neonates and 17,143 children admitted during the 2-year stepped crossover period (November 2015 to October 2017). Compared to the pulse oximetry period, the full oxygen system had no association with death for children (adjusted odds ratio [aOR] 1.06; 95% confidence interval [CI] 0.77-1.46; p = 0.721) or children with ALRI (aOR 1.09; 95% CI 0.50-2.41; p = 0.824) and was associated with an increased risk of death for neonates overall (aOR 1.45; 95% CI 1.04-2.00; p = 0.026) but not preterm/low-birth-weight neonates (aOR 1.30; 95% CI 0.76-2.23; p = 0.366). Secondary analyses suggested that the introduction of pulse oximetry improved oxygen practices prior to implementation of the full oxygen system and was associated with lower odds of death for children with ALRI (aOR 0.33; 95% CI 0.12-0.92; p = 0.035) but not for children, preterm neonates, or neonates overall (aOR 0.97, 95% CI 0.60-1.58, p = 0.913; aOR 1.12, 95% CI 0.56-2.26, p = 0.762; aOR 0.90, 95% CI 0.57-1.43, p = 0.651). Limitations of our study are a lower-than-anticipated power to detect change in mortality outcomes (low event rates, low participant numbers, high intracluster correlation) and major contextual changes related to the 2016-2017 Nigerian economic recession that influenced care-seeking and hospital function during the study period, potentially confounding mortality outcomes. CONCLUSIONS: We observed no mortality benefit for children and a possible higher risk of neonatal death following the introduction of a multifaceted oxygen system compared to introducing pulse oximetry alone. Where some oxygen is available, pulse oximetry may improve oxygen usage and clinical outcomes for children with ALRI. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12617000341325.

N-acetyltransferase 2 enzyme genotype-phenotype discordances in both HIV-negative and HIV-positive Nigerians.

BACKGROUND: The N-acetyltransferase 2 (NAT2) enzyme has been understudied in Nigerians including genotype-phenotype association studies. OBJECTIVE: The aim of this study was NAT2 haplotype identification and genotype-phenotype investigations in HIV-positive and HIV-negative Nigerians. PATIENTS AND METHODS: Phenotypes included self-reported sulphonamide hypersensitivity survey, experimental and computational NAT2 phenotyping. The NAT2 gene was amplified by PCR. Gene sequencing used ABI 3730 and Haploview 4.2 for haplotype reconstruction. Genotype-phenotype analyses used the χ P-value and odds ratio with a 95% confidence interval. RESULTS: Self-reported sulphonamide hypersensitivity showed a prevalence of 3.1 and 12.4% in HIV-positive and HIV-negative Nigerians, respectively. NAT2 genetic variants 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G and 857G>A were not significantly different between both groups (odds ratio=0.87; 95% confidence interval: 0.54-1.38, P=0.55). Nine haplotypes: NAT2*4, NAT2*12A, NAT2*13A, NAT2*5B, NAT2*6A, NAT2*7B, NAT2*5C, NAT2*14B and NAT2*14A had frequencies more than 1%, whereas NAT2*12B had 1.1% in the HIV-positive and 0.4% in the HIV-negative group. Overall, slow acetylator haplotypes made up 68%. The NAT2*12 signature single-nucleotide polymorphism was in high linkage disequilibrium with signature single-nucleotide polymorphism for NAT2*13 (D'=0.97, r=0.61) and NAT2*5 (D'=0.98, r=0.64). Genotype-phenotype association analysis showed haplotypes NAT2*13A, NAT2*5C, NAT2*7B and NAT2*14A to be associated strongly with the slow metabolic phenotype (P=0.002, 0.029, 0.032 and 0.050, respectively). Computational phenotypes were similar, with 30.9, 66 and 3.1% for slow, intermediate and rapid acetylators, respectively, among HIV-positive Nigerians and 31.2, 66.3 and 2.5% among the HIV-negative group. Overall, slow phenotypes made up 31%. CONCLUSION: NAT2 haplotype frequencies are similar in Nigerians, irrespective of HIV status, but genotype-phenotype discordances exist.

Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria.

BACKGROUND: Early rising asexual parasitaemia (ERAP), initially defined as 'an increase in the parasite count over the baseline pre-treatment level during the first 24 h of treatment' of falciparum malaria with artemisinin derivatives is well documented, but there is no characterization of its risk factors, kinetics, molecular features or relationship to late-appearing anaemia (LAA) in acute falciparum malaria in African children following oral artemisinin-based combination therapies (ACTs). METHODS: ERAP was defined as ≥5% increase in pre-treatment parasitaemia within 8 h of initiating treatment. Parasitaemia was quantified pre-treatment and 1-2 hourly for 8 h, and less frequently thereafter for 6 weeks following randomized treatment of acutely malarious children with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine. Risk factors were determined by stepwise multiple logistic regression model. Kinetics of release into and of elimination of asexual parasites and DNA clones from peripheral blood were evaluated by method of residuals and non-compartment model, respectively. Parasite population changes were evaluated morphologically and by molecular genotyping. RESULTS: ERAP occurred in 205 of 416 children. A parasitaemia <100,000/µL and parasitaemia 1 day post-treatment initiation were independent predictors of ERAP. In children with ERAP: mean and peak time of increase in parasitaemia were 105.6% (95% CI 81-130.1) and 2.5 h (95% CI 2.2-2.7), respectively. Mean lag time, half-time and rate constant of release were 0.2 h (95% CI 0.2-0.3), 1 h (95% CI 0.9-1.1), and 0.9 h-1 (95% CI 0.8-1), respectively. Schizonts and young gametocytes were seen only in peripheral blood of few children with ERAP. In age-, gender-, baseline parasitaemia- and treatment-matched children with and without ERAP, parasite DNA clearance time and area under curve of number of DNA clones versus time were significantly higher in children with ERAP indicating peripheral retention of released parasites followed by elimination. DNA clone elimination was monoexponential. CONCLUSION: ERAP is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose of ACTs of acute childhood falciparum malaria. TRIALS REGISTRATION: Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015.

Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials.

BACKGROUND: Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children. METHODS: Malarious <5 year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6 weeks. Anaemia was defined as haematocrit <30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28-42 days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28-42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit <30% occurring within 1 week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH >4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively. RESULTS: Pre-treatment, 355 of 959 children were anaemic. Duration of illness >2 days and parasitaemia ≤10,000 µL-1 were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age ≤ 15 months, history of fever pre-treatment and enrolment haematocrit ≤35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH >4% occurred in 446 of 694 children; its predictors were anaemia pre-treatment, enrolment parasitaemia ≤50,000 µL-1, parasitaemia one day post-treatment initiation and gametocytaemia. DAFH >4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1 day post-treatment initiation, haematocrit ≥37%, and parasitaemia >100,000 µL-1. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9-2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children. CONCLUSION: After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH >4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR) [ PACTR201709002064150, 1 March 2017 ].

Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria.

BACKGROUND: Late-appearing anaemia (LAA) following treatment with artemisinins for severe malaria has been reported and well described, but there are limited clinical and parasitological data on LAA in African children with uncomplicated falciparum malaria following oral artemisinin-based combination therapies (ACTs). METHODS: This was an open label study with the main objectives of evaluating the clinical features, the risk factors for, the temporal changes in haematocrit and the outcomes of a LAA in malarious children treated with artesunate-amodiaquine (AA), artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHP). The diagnosis of LAA was made using the criteria: clearance of parasitaemia, fever and other symptoms within 1 week of commencing treatment; adequate clinical and parasitological response at 4-6 weeks after treatment began; haematocrit ≥30 % 1 and/or 2 weeks after treatment began; and haematocrit <30 %, parasite negativity by microscopy and polymerase chain reaction and absence of concomitant illness 3-6 weeks after treatment began. RESULTS: LAA occurred in 84 of 609 children, was mild, moderate or severe in 77, 6 or 1 child, respectively and was relatively asymptomatic. Mean time elapsing from commencement of treatment to LAA was 27.1 days (95 % CI 25.3-28.9). In a multivariate analysis, an age <3 years (adjusted odd ratio [AOR] = 2.6, 95 % CI 1.3-5.2, P = 0.005), fever 1 day after treatment began (AOR = 3.8, 95 % CI 1.8-8.2, P < 0.0001), haematocrit <25 % at presentation (AOR = 2.2, 95 % CI 1.3-3.7, P = 0.003), haematocrit <30 % 1 day after treatment began (AOR = 2.1, 95 % CI 1.0-4.3, P = 0.04), parasite reduction ratio >10(4) 2 days after treatment began (AOR = 2.1, 95 % CI 1.1-3.9, P = 0.03) and spleen enlargement at presentation (AOR = 2.0, 95 % CI 1.1-3.9, P < 0.0001) were independent predictors of LAA. During 6 weeks of follow-up, uneventful recovery from anaemia occurred in 56 children [mean recovery time of 11.8 days (95 % CI 10.3-13.3)]. The only independent predictor of failure of recovery was LAA occurring 4 weeks after starting treatment (AOR = 7.5, 95 % CI 2.5-22.9, P < 0.0001). CONCLUSION: A relatively asymptomatic LAA with uneventful recovery can occur in young malarious children following ACTs. Its occurrence may have implications for case and community management of anaemia and for anaemia control efforts in sub-Saharan Africa where ACTs have become first-line antimalarials. TRIALS REGISTRATION: Pan African Clinical Trial Registry PACTR201508001188143, 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015 http://www.pactr.org .

Temporal changes in haematocrit following artemisinin-based combination treatments of uncomplicated falciparum malaria in children.

BACKGROUND: Artemisinin-based combination treatments (ACTs) or intravenous artesunate are used in over 100 countries for uncomplicated or severe falciparum malaria. Although intravenous artesunate may cause delayed haemolytic anaemia, there is little evaluation of the temporal changes in haematocrit following ACTs. METHODS: Clinical and parasitological parameters were measured before and following treatment of uncomplicated falciparum malaria in children with artesunate-amodiaquine (AA) or artemether-lumefantrine (AL) over 6-weeks. Changes in haematocrit were characterized in individual patients based on a haematocrit <30 % or ≥30 % before and following treatment. Kinetics of the deficit in haematocrit from <30 % until attainment of ≥30 % were estimated by a non-compartment model. RESULTS: In 248 of 1180 children eligible for evaluation, common temporal patterns were: no change or increase in haematocrit from ≥ 30 % [50 % of patients], haematocrit >30 % at presentation declining to <30 % within 2 weeks (early monophasic fall) [19 % of patients], and haematocrit <30 % at presentation increasing to ≥ 30 % [23 % of patients]. Haematocrit >30 % at presentation declining to <30 %, 3-5 weeks later (late monophasic fall) occurred in 7 children (3 %). Fall in haematocrit ≥5 units following treatment occurred in 57 children [23 %] between 14 and 28 days after treatment began. Baseline parasitaemia and proportion with > 100,000µL(-1) asexual forms were significantly higher in children with ≥5 units compared to <5 units fall in haematocrit 21 or 28 days after treatment began. Irrespective of pattern, declines in haematocrit deficit from <30 % were mono-exponential, with similar half-times for AA- and AL-treated children (1.32 d versus 1.14 d). Anaemia half-time correlated significantly positively with anaemia recovery time in the same patients (r = 0.55, P < 0.0001). Bland-Altman analysis of 9 or 10 multiples of anaemia half-time and anaemia recovery times showed narrow limit of agreement with insignificant biases (P = 0.19 or 0.63, respectively). CONCLUSIONS: In uncomplicated falciparum malaria, increases or falls in haematocrit are common following ACTs. Falls in haematocrit ≥ 5 units are common and may or may not result in early or late anaemia. In children who recovered from acute falciparum malaria-associated anaemia following ACTs, decline in haematocrit deficit is mono-exponential. TRIALS REGISTRATION: Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201508001191898 , 7 July 2015 http://www.pactr.org .

Pneumonia hospitalizations and mortality in children 3 - 24-month-old in Nigeria from 2013 to 2020: Impact of pneumococcal conjugate vaccine ten valent (PHiD-CV-10).

Pneumococcal conjugate vaccine ten valent (PCV 10) was introduced into Nigeria in three phases. Phase 3 introduction started in August 2016. However, its impact on pneumonia admissions and mortality among vaccinated Nigerian children has not been determined. Data in the period before PCV-10 introduction (3 August 2013-2 August 2016), and after (3 August 2017-2 August 2020) were retrospectively extracted from the medical charts of eligible patients aged 3-24 months with hospitalized radiological pneumonia at the University College Hospital (UCH), Ibadan; National Hospital (NH), Abuja; and Federal Teaching Hospital (FTH), Gombe, allowing for an intervening period of 1 year. Proportions of the patients with hospitalized pneumonia and case fatality rates were determined during both periods. The results were compared using z-test, multiple logistic regression analysis and p < .05 was considered significant. Adjusted pneumonia hospitalization rates between the two periods increased at the NH Abuja (10.7% vs 14.6%); decreased at the UCH, Ibadan (8.7% vs 6.9%); and decreased at the FTH, Gombe (28.5% vs 18.9%). Case fatality rates decreased across all the sites during the post-PCV introduction period: NH Abuja, from 6.6% to 4.4% (p = .106); FTH, Gombe, 11.7% to 7.7% (p = .477); and UCH, Ibadan, 2.0% to 0% (p = .045); but only significant at Ibadan. Overall, proportion of hospitalized pneumonia cases decreased after 3 years of PCV 10 introduction into the National Immunization Programme in Nigeria. The case fatality rate during post-PCV 10 introduction decreased at all the three sites, but this difference was significant at the UCH, Ibadan.

Pneumonia is the commonest killer of Nigerian children aged less than 5 years. Pneumonia vaccine (PCV 10) was introduced into Nigeria Vaccination Program between 2014 and 2016, but up till now the value has not been confirmed. We conducted a retrospective study in which data before and after PCV 10 introduction were compared. The study sites were the University College Hospital (UCH), Ibadan; National Hospital (NH), Abuja; and Federal Teaching Hospital (FTH), Gombe. The data were extracted from the medical charts of eligible patients aged 3­24 months who were admitted for severe pneumonia with evidences on lung radiographs. We found that the proportion of hospitalized pneumonia cases decreased after 3 years of PCV 10 introduction into the National Immunization Program in Nigeria. The death rate during post-PCV 10 introduction decreased at all the three sites, but was only significantly decreased at the UCH, Ibadan.

Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.

The role of routine post-natal abdominal ultrasound for newborns in a resource-poor setting: a longitudinal study.

BACKGROUND: Neonatal abdominal ultrasound is usually performed in Nigeria to investigate neonatal symptoms rather than as a follow up to evaluate fetal abnormalities which were detected on prenatal ultrasound. The role of routine obstetric ultrasonography in the monitoring of pregnancy and identification of fetal malformations has partly contributed to lowering of fetal mortality rates. In Nigeria which has a high maternal and fetal mortality rate, many pregnant women do not have ante-natal care and not infrequently, women also deliver their babies at home and only bring the newborns to the clinics for immunization. Even when performed, most routine obstetric scans are not targeted towards the detection of fetal abnormalities.The aim of the present study is to evaluate the benefit of routinely performing abdominal scans on newborns with a view to detecting possible abnormalities which may have been missed ante-natally. METHODS: This was a longitudinal study of 202 consecutive, apparently normal newborns. Routine clinical examination and abdominal ultrasound scans were performed on the babies by their mother's bedside, before discharge. Neonates with abnormal initial scans had follow-up scans. RESULTS: There were 108 males and 94 females. There were 12 (5.9%) abnormal scans seen in five male and seven female neonates. Eleven of the twelve abnormalities were in the kidneys, six on the left and five on the right. Three of the four major renal anomalies- absent kidney, ectopic/pelvic kidney and two cases of severe hydronephrosis were however on the left side. There was one suprarenal abnormality on the right suspected to be a possible infected adrenal haemorrage. Nine of the abnormal cases reported for follow- up and of these, two cases had persistent severe abnormalities. CONCLUSIONS: This study demonstrated a 5.9% incidence of genito urinary anomalies on routine neonatal abdominal ultrasound in this small population. Routine obstetric USS is very useful but inadequate availability of skilled personnel and cost implications create great challenges in poor resource settings like Nigeria. However, awareness should be created so that parents who can afford such investigations can make informed decisions.

Oxygen systems and quality of care for children with pneumonia, malaria and diarrhoea: Analysis of a stepped-wedge trial in Nigeria.

OBJECTIVES: To evaluate the effect of improved hospital oxygen systems on quality of care (QOC) for children with severe pneumonia, severe malaria, and diarrhoea with severe dehydration. DESIGN: Stepped-wedge cluster randomised trial (unblinded), randomised at hospital-level. SETTING: 12 hospitals in south-west Nigeria. PARTICIPANTS: 7,141 children (aged 28 days to 14 years) admitted with severe pneumonia, severe malaria or diarrhoea with severe dehydration between January 2014 and October 2017. INTERVENTIONS: Phase 1 (pulse oximetry) introduced pulse oximetry for all admitted children. Phase 2 (full oxygen system) (i) standardised oxygen equipment package, (ii) clinical education and support, (iii) technical training and support, and (iv) infrastructure and systems support. OUTCOME MEASURES: We used quantitative QOC scores evaluating assessment, diagnosis, treatment, and monitoring practices against World Health Organization and Nigerian standards. We evaluated mean differences in QOC scores between study periods (baseline, oximetry, full oxygen system), using mixed-effects linear regression. RESULTS: 7,141 eligible participants; 6,893 (96.5%) had adequate data for analysis. Mean paediatric QOC score (maximum 6) increased from 1.64 to 3.00 (adjusted mean difference 1.39; 95% CI 1.08-1.69, p<0.001) for severe pneumonia and 2.81 to 4.04 (aMD 1.53; 95% CI 1.23-1.83, p<0.001) for severe malaria, comparing the full intervention to baseline, but did not change for diarrhoea with severe dehydration (aMD -0.12; 95% CI -0.46-0.23, p = 0.501). After excluding practices directly related to pulse oximetry and oxygen, we found aMD 0.23 for severe pneumonia (95% CI -0.02-0.48, p = 0.072) and 0.65 for severe malaria (95% CI 0.41-0.89, p<0.001) comparing full intervention to baseline. Sub-analysis showed some improvements (and no deterioration) in care processes not directly related to oxygen or pulse oximetry. CONCLUSION: Improvements in hospital oxygen systems were associated with higher QOC scores, attributable to better use of pulse oximetry and oxygen as well as broader improvements in clinical care, with no negative distortions in care practices. TRIAL REGISTRATION: ACTRN12617000341325.

The international Perinatal Outcomes in the Pandemic (iPOP) study: protocol.

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread "natural experiment" of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic.

Is caffeine available and affordable in low and middle-income countries? A survey in sub-Saharan Africa.

Caffeine is the preferred pharmacologic treatment for apnea of prematurity. Little is known about the availability and affordability of caffeine in the low and middle-income countries of sub-Saharan Africa (SSA). We conducted an online survey in 2020 of newborn physicians in SSA to determine their access to caffeine. Of 90 invited participants, 55 responded (61%). They worked in 13 SSA countries and 48 hospitals. Caffeine was used in 6 countries. In 5 of these countries, the price of caffeine was reported and ranged from US $1.73 in Ghana to US $73.63 in Kenya per 3 mL vial. High drug prices and lack of drug availability for purchase were identified most frequently as primary barriers. Some respondents believed that other methylxanthines are adequate substitutes for caffeine. Only 31 of 53 (58%) respondents knew that caffeine is included in the essential drug list of the World Health Organization (WHO).

Diagnosis of pneumonia and malaria in Nigerian hospitals: A prospective cohort study.

BACKGROUND: Pneumonia and malaria are the leading causes of global childhood mortality. We describe the clinical presentation of children diagnosed with pneumonia and/or malaria, and identify possible missed cases and diagnostic predictors. METHODS: Prospective cohort study involving children (aged 28 days to 15 years) admitted to 12 secondary-level hospitals in south-west Nigeria, from November 2015 to October 2017. We described children diagnosed with malaria and/or pneumonia on admission and identified potential missed cases using WHO criteria. We used logistic regression models to identify associations between clinical features and severe pneumonia and malaria diagnoses. RESULTS: Of 16 432 admitted children, 16 184 (98.5%) had adequate data for analysis. Two-thirds (10 561, 65.4%) of children were diagnosed with malaria and/or pneumonia by the admitting doctor; 31.5% (567/1799) of those with pneumonia were also diagnosed with malaria. Of 1345 (8.3%) children who met WHO severe pneumonia criteria, 557 (41.4%) lacked a pneumonia diagnosis. Compared with "potential missed" diagnoses of severe pneumonia, children with "detected" severe pneumonia were more likely to receive antibiotics (odds ratio [OR], 4.03; 2.63-6.16, P < .001), and less likely to die (OR, 0.72; 0.51-1.02, P = .067). Of 2299 (14.2%) children who met WHO severe malaria criteria, 365 (15.9%) lacked a malaria diagnosis. Compared with "potential missed" diagnoses of severe malaria, children with "detected" severe malaria were less likely to die (OR, 0.59; 0.38-0.91, P = 0.017), with no observed difference in antimalarial administration (OR, 0.29; 0.87-1.93, P = .374). We identified predictors of severe pneumonia and malaria diagnosis. CONCLUSION: Pneumonia should be considered in all severely unwell children with respiratory signs, regardless of treatment for malaria or other conditions.

Providing oxygen to children and newborns: a multi-faceted technical and clinical assessment of oxygen access and oxygen use in secondary-level hospitals in southwest Nigeria.

BACKGROUND: Oxygen is an essential medical therapy that is poorly available globally. We evaluated the quality of oxygen therapy in 12 secondary-level Nigerian hospitals, including access to oxygen equipment, equipment functionality, healthcare worker knowledge and appropriateness of use. METHODS: We conducted a three-part evaluation of oxygen access and use involving: (1) facility assessment (including technical evaluation of oxygen equipment), (2) clinical audit (children and neonates admitted January 2014-December 2015) and (3) survey of healthcare worker training and experience on the clinical use of oxygen (November 2015). RESULTS: Oxygen access for children and newborns is compromised by faulty equipment, lack of pulse oximetry and inadequate care practices. One hospital used pulse oximetry for paediatric care. Eleven hospitals had some access to oxygen supplies. Testing of 57 oxygen concentrators revealed two (3.5%) that were 'fit for use'. Overall, 14.4% (3708/25 677) of children and neonates received oxygen some time during their admission; 19.4% (1944/10 000) of hypoxaemic children received oxygen; 38.5% (1217/3161) of children who received oxygen therapy were not hypoxaemic. CONCLUSIONS: Oxygen access for children in Nigerian hospitals is poor, and likely results in substantial excess mortality. To improve oxygen access for children globally we must focus on actual provision of oxygen to patients-not simply the presence of oxygen equipment at the facility level. This requires a systematic approach to improve both oxygen (access [including equipment, maintenance and affordability]) and oxygen use (including pulse oximetry, guidelines and continuing education).